The present invention relates to the use of gangliosides, particularly a mixture of gangliosides, to treat autonomic nervous system abnormalities caused by Chagas' disease or American trypanosomiasis.
Chagas' disease or American trypanosomiasis is the most common cause of congestive heart failure and sudden death in the world and represents a major public health problem in Latin America. Trypanosoma cruzi, the etiologic agent of Chagas' disease, and its insect vectors have an extensive geographic distribution encompassing South and Central America, and extending to the southwestern and southeastern United States. The majority of patients, 90 to 95 percent, survive the acute phase of the illness which usually occurs in childhood. These patients then enter into a latent phase of the disease in which there are no clinical signs or symptoms related to T. cruzi infection. All patients exhibit positive serologic tests for T. cruzi. Recently, advanced cardiologic techniques have demonstrated subtle and potentially progressive functional and morphologic cardiac abnormalities in this phase of Chagas' disease Electrocardiographic studies have shown conduction system abnormalities and echocardiographic studies have documented impaired left ventricular function in asymptomatic patients Histopathologic studies using endomyocardial biopsies or tissues from chagasic patients who died of causes other than Chagas' disease have documented inflammatory lesions, fibrosis and degenerative changes of the myocardium. These findings have led many investigators to believe that a smouldering, slowly progressive destruction of the myocardium occurs in the latent phase which results in the severe myocardial pathology seen in the chronic phase of Chagas' disease
Approximately 20 to 30 percent of T. cruzi infected patients progress to the chronic phase of Chagas' disease which is manifested by signs and symptoms of congestive heart failure and cardiac arrhythmias. The majority of patients are from 30 to 50 years of age and complain of symptoms consistent with congestive heart failure. Physical examination reveals signs of both right and left sided congestive heart failure. Electrocardiograms (ECG) typically show conduction defects, most notably right bundle branch block and/or left anterior hemiblock. Arrhythmias are commonly noted. Chest x-rays (CXR) reveal moderate to severe cardiomegaly. Once the onset of congestive heart failure is noted, the use of cardiotonic drugs, diuretics, or the implantation of pacemakers have been ultimately to no avail. Patients inexorably deteriorate with a mortality rate of greater than 90% within 5 years of the onset of cardiac symptoms. Pathologic examination of the hearts of patients who died from chronic Chagas' disease shows a markedly enlarged heart with dilation of all 4 chambers and areas of focal inflammation with myofiber destruction and fibrosis are evident.
Histopathologic examination of hearts from patients who died of chronic Chagas' disease sometimes reveals neuronal lesions. Reports have described the destruction of parasympathetic ganglia and their subsequent fibrosis in both the presence and absence of inflammatory cells, and have showed mononuclear cell lesions with interrupted and broken axis cylinders and perineuronal inflammation in chronic chagasic hearts, including neuronophagia of intracardiac ganglioneurons. Not surprisingly, patients with Chagas disease often show autonomic nervous system dysfunction. Reports have also documented abnormal responses to postural changes using the Valsalva maneuver exercise-related heart rate response; and infusion of pharmacologic agents such as atropine or Beta-blockers. The abnormal responses were noted in asymptomatic chagasic patients as well as in chagasic patients with signs or symptoms of congestive heart failure. Other investigators have reported similar findings, and have shown abnormal baroreceptor responses to phenylephrine administration, Valsalva maneuver, or hyperventilation testing.
The etiology of the neuronal lesions and autonomic nervous system dysfunction in Chagas' disease is unclear. Several theories have been proposed to explain these observations. It has been postulated that T. cruzi produces a neurotoxin that preferentially destroys the sympathetic nervous system and the parasympathetic nervous system of the heart. Some have reported the presence of a circulating antibody in the sera of patients with Chagas' disease that binds to nerve cells and have hypothesized that the neuronal lesions are autoimmune in nature. Unfortunately, to date, no good experimental or clinical evidence exists to establish the pathogenesis of the neuronal lesions seen in Chagas' disease.
The severe complications and widespread occurrence of Chagas' disease present a great need for a method to treat the disease and prevent its effects. It is this great need which is addressed and met by the present invention.